Prioritizing pharmacokinetic drug interaction precipitants in natural products: application to OATP inhibitors in grapefruit juice

Abstract

Natural products, including botanical dietary supplements and exotic drinks, represent an ever-increasing share of the health care market. The parallel ever-increasing popularity of self-medicating with natural products increases the likelihood of co-consumption with conventional drugs, raising concerns for unwanted natural product-drug interactions. Assessing the drug interaction liability of natural products is challenging due to the complex and variable chemical composition inherent to these products, necessitating a streamlined preclinical testing approach to prioritize precipitant individual constituents for further investigation. Such an approach was evaluated in the current work to prioritize constituents in the model natural product, grapefruit juice, as inhibitors of intestinal organic anion-transporting peptide (OATP)-mediated uptake. Using OATP2B1-expressing MDCKII cells and the probe substrate estrone 3-sulfate, IC50s were determined for constituents representative of the flavanone (naringin, naringenin, hesperidin), furanocoumarin (bergamottin, 6′,7′-dihydroxybergamottin), and polymethoxyflavone (nobiletin and tangeretin) classes contained in grapefruit juice juice. Nobiletin was the most potent (IC50, 3.7 μM); 6′,7′-dihydroxybergamottin, naringin, naringenin, and tangeretin were moderately potent (IC50, 20–50 μM); and bergamottin and hesperidin were the least potent (IC50, >300 μM) OATP2B1 inhibitors. Intestinal absorption simulations based on physiochemical properties were used to determine ratios of unbound concentration to IC50 for each constituent within enterocytes and to prioritize in order of pre-defined cut-off values. This streamlined approach could be applied to other natural products that contain multiple precipitants of natural product-drug interactions.

Inhibitory Effects of Quercetin and Its Main Methyl, Sulfate, and Glucuronic Acid Conjugates on Cytochrome P450 Enzymes, and on OATP, BCRP and MRP2 Transporters

“…Organic anion-transporting polypeptides (OATPs) are solute carrier membrane transporters. They have a major role in the absorption, tissue distribution, and elimination of endogenous molecules (e.g., steroids, bile acids, and bilirubin), drugs (e.g., statins), food components (e.g., Q and naringin), and toxins (e.g., alpha-amanitin and ochratoxin A) [ 18 , 19 , 20 , 21 , 22 ]. OATP1B1, OATP1B3, and OATP2B1 appear in hepatocytes [ 23 ]; furthermore, OATP1A2 and OATP2B1 are involved in the uptake of their substrates into enterocytes and/or the central nervous system [ 19 , 24 , 25 , 26 ].…”

Potential Risk of Food-Drug Interactions: Citrus Polymethoxyflavones and Flavanones as Inhibitors of the Organic Anion Transporting Polypeptides (OATP) 1B1, 1B3, and 2B1

“…OATP inhibitors can decrease (inhibition of intestinal OATP2B1) or increase (inhibition of hepatic OATP1B1/1B3) plasma concentrations of substrate drugs triggering drug-drug or food-drug interactions [17][18][19][20][21][22][23]. In contrast to the widely expressed OATP2B1, for which inhibition by citrus fruit/juice/flavonoids provoking interactions with drugs has already been demonstrated [19,23,24], the role of the liver-specific OATP1B1 and OATP1B3 in mediating citrus-drug interactions is less clear, and the effect of polymethoxyflavones and the 7-O-rutinoside-flavanones on these transporters is completely unknown. We therefore investigated in vitro whether the 7-O-rutinoside-flavanones and the polymethoxyflavones could inhibit human OATP1B1 and OATP1B3 and also tested OATP2B1 inhibition, which was so far untested for sinensetin, didymin, and narirutin.…”

Revisiting the role of gut wall in the fate of orally administered drugs: Why now and to what effect?

“…). The themes issue concludes with two further applications of relatively more complex models that explore intestinal metabolism, transport and associated interactions by Johnson et al and Liu et al . The latter helps readers to appreciate why a closer collaboration between the DMPK and pharmaceutics groups is essential in understanding aspects related to gut wall handling of drugs and associated drug interactions.…”

“…Accordingly, the mechanism of the food effect is not limited to dissolution, solubility and gastro‐ empting rate matters but also to inhibition and induction of transporters and enzymes. Johnson et al analyze the effect of food using grapefruit on OATP2B1, which was demonstrated previously to be an intestinal drug uptake transporter by Tamai and Nakanishi in 2013 .…”

“…The selection between complex vs. simplistic models always depends on the question in hand. Some applications of higher level models are demonstrated by Johnson et al as well as by Liu et al . For instance, Liu et al use such models for bringing the formulation into play.…”